delta3,5-pregnadiene derivatives



United States Patent 3,099,657 A -PREGNADIENE DERIVATIVES John A.Zderic, Palo Alto, Calif., Otto Halpern, Mexico City, Mexico, and JoseIriarte, Zurich, Switzerland, assignors, by mesne assignments, to SyntexCorporation, a corporation of Panama N0 Drawing. Filed Feb. 26, 1962,Ser. No. 175,811 17 Claims. (Cl. 260239.55)

The present invention relates to novel cyclopentanophenanthrenederivatives and to a process for the production thereof.

More particularly the present invention relates to novel 6-methyl-A-pregnadiene derivatives.

The novel compounds of the present invention which are progestationalagents with anti-estro-genic, antigonadotrophic and anti-ovulatoryproperties are represented by the following formula:

CHzY

CH3 In the above formula Y represents hydrogen or fluorine; R representshydrogen or methyl; R represents hydroxyl or a hydrocarbon carboxylieacyloxy group of less than 12 carbon atoms; R represents hydrogen,or-methyl, B methyl, a-hydroxy or a-acyloxy; in addition R and Rtogether may represent the group:

wherein P may be a lower alkyl group and Q represents ,a lower alkyl, oran aryl or aralkyl group, each of up to 8 carbon atoms.

The acyloxy groups are derived {from hydrocarbon carboxylic acidscontaining less than 12 carbon atoms which may be saturated orunsaturated, of straight, branched, cyclic or cyclic-aliphatic chain,aromatic and may be substituted by functional groups such as hydroxy,alkoxy containing up to 5 carbon atoms, acyloxy containing up to 12carbon atoms, nitro, amino or halogen.

Typical ester groups are the acetate, propionate, enanthate, benzoate,trimethylacetate, t-butylacetate, phenoxyacetate, cyclopentylpropionate,aminoacetate and ,6- chloropropionate.

The novel compounds of the present invention are prepared by the processexemplified by the following equation:

CHiY

-..R4 iMNRE CHzY HO- HO 3,099,657 Patented July 30, 196.3

"ice

C'HzY CHzY ..32 M Pal,

no no 1v) Ho Me '0 CHzY In the above formulas Y, R and R have the samemeaning as previously described, R represents a hydrocarbon carboxylic.acyloxy group of less than 12 carbon atoms; R represents hydrogen,oc-DlthYl; B-methyl or a-acyloXy; in addition R and R together representthe wherein P and Q have the same meaning as previously set forth and Acrepresents the acetyl group. There are also contemplated within thescope of the present invention compounds wherein R and R representhydrogen.

In practicing the process outlined above, the starting compound which isa A -pregnen-3 3-ol-2O-one derivative (I) is treated with ethyleneglycol to form the corresponding 2O-cycloethylenedioxy-A -pregnen-35-01derivative (II). This compound is treated with an organic peracid,preferably with monoperphthalic acid, thus yielding the respective20-cycl0ethylenedioxy-5ot, 6ot-oxido pregnan-Iafi-ol compound (III),which upon reaction with a methyl magnesium halide, preferably thebromide, affords the corresponding 20-cycloethylenedioxy-6/imethylpregnan 5a,3,B diol(IV). The latter is conventionally acylated,preferably with acetic anhydride in pyridine, to give the respective3fl-monoaicetate (V) which upon treatment with acetic anhydride in thepresence of an acid, preferably sulfuric acid, furnishes thecorresponding 6-methyl-A -pregnen-3/3-ol-2O one acetate (VI). TheB-acetate group is hydrolyzed by reaction in a mild basic medium to givethe corresponding 3fi-hydroxy steroid (VII). Conventional tosylation ofthis 3-alcohol in pyridine, followed by treatment of the resulting3-tosylate (VIH) with sodium acetate in acetic acid yields thecorresponding 6-methyl-A -pregnadien-20-one compound (IX).

The compounds obtained by the above described procedures, which have a17a-acyloxy group present in the molecule, yield the correspondingl7oc-f1'66 hydroxyl derivative by conventional saponification,preferably with an alkali metal hydroxide.

The final compounds of the present invention having a ketonide at the16,17-positions produce the 1611,1706- diols by hydrolysis with a strongacid, preferably formic acid.

The free alcohols thus obtained are conventionally acylated with anexcess of an acylating agent, as for example an anhydride derived from ahydrocarbon carboxylic acid of the type described hereinbefore in thepresence of p-toluenesulfonic acid, thus affording correspondingly thel7a-monoacylates or the 16a,17a-diacylates. The latter compounds, uponselective saponification in a mild alkaline medium yield thecorresponding 16a-hydroxy-17a-acyloxy derivative which by furtherconventional acylation gives the respective 16,17-diesters with the sameor different ester groups.

Alternatively, conventional acylation of the 16a,l7udiol in the absenceof p-toluenesulfonic acid yields the corresponding 16oz acryloxy 17cchydroxy compound which upon further conventional acylation in thepresence of p-toluenesulfonic acid with the same or a difierentacylating agent gives the corresponding 16,17-diester with the same ordifferent ester groups.

The following specific examples serve to illustrate but are not intendedto limit the scope of the present invention:

PREPARATION 1 The compounds 16a-methyl-A -pregnene-3B,17a-diol- 20one-17-acetate, 16fi-methyl-A -pregnene-3 [3,1711 diol-20-one-17-acetate, 19 nor-A -pregnene-3 8-ol-2O-one and A -pregnen3fi,16a,17u triol 20-one 16,17-acetophenonide were prepared inaccordance with Zderic et al. US. patent application Serial No. 164,626,filed January 5, 1962, now Patent No. 3,071,581.

PREPARATION 2 A culture of Streptomyces roseochromogenus ATCC 3347 wasprepared in an inclined agar medium containing 1% of glucose and 1% ofyeast extract. 1 cc. of a suspension of this culture was then used toinnoculate each one of a series of 250 cc. flasks containing 50 cc. of asterilized aqueous medium of 2% peptone and 5% corn syrup, the mixtureswere then incubated in a shaking machine at 28 C. under aeration for aperiod of 2448 hours. There was thus obtained a vegetating growingculture of Streptomyces roseochromogenus which was used for thesubsequent incubation of the steroid.

10 mg. of 19-nor-A pregnen-3B-ol-20-one-acetate (obtained byconventional acetylation of the free 3,8-alcohol) were added to each 50cc. of the vegetating culture of Streptomyces roseochromogenus, obtainedas described above. The mixture was stirred for 48-72 hours withaeration and then extracted several times with methylene dichloride. Theextract was washed with water, dried over anhydrous sodium sulfate,filtered and evaporated under reduced pressure.

The residue was purified by chromatography on silica gel thus giving19-nor-A -pregnene-3p,16a-diol-20-one-3- acetate.

A solution of '8 g. of the latter steroid in cc. of chloroformcontaining a few drops of pyridine was cooled to 0 C. and slowly treatedunder stirring with a cooled solution of chloride in chloroformcontaining 1.05 molar equivalents of chlorine. The mixture was allowedto reach room temperature, the excess of chlorine was re moved byflushing with dry air and the solution was washed with 5% aqueous sodiumbicarbonate solution and subsequently with water, dried over anhydroussodium sulfate and evaporated to dryness. Crystallization of the residuefrom methanol-benzene afforded 50:,6fidichloro-19-nor-pregnane- 35,16a-diol-20-one-3-acetate.

A solution of 5 g. of the latter 50c, 6,6-dichloro compound in 25 cc. ofpyridine was cooled to 0 C. Under stirring there was added 1.3 g. oftosyl chloride, the mixture was kept for 16 hours at 0 C., diluted with100 cc. of chloroform, washed with dilute hydrochloric acid, water,aqueous sodium bicarbonate solution and again with water, dried overanhydrous sodium sulfate and then evaporated to dryness under reducedpressure. Thus there was obtained the crude5a,6fi-dichloro-19-nor-pregname-318,16a-diol-20-one-3-acetate-l6-tosylate.

The total crude compound was kept at 50 C. with 5 g. of anhydrous sodiumacetate and 160 cc. of ethanol during 2.5 hours. Chloroform and waterwere added. The aqueous layer was extracted several times withchloroform and the combined organic extracts were washed withconcentrated sodium bicarbonate solution, then with water, dried oversodium sulfate and evaporated to dryness. Chromatography andrecrystallization of the solid fractions from acetone-hexane afforded5u,6 8-dichloro- 19-nor-A -pregnen-3/3-ol-2O-one-acetate.

50 cc. of dioxane containing 3 g. of the latter steroid and 3.46 cc. ofpyridine were allowed to stand at room temperature for 6 days with 2.0g. of osmium tetroxide. The mixture was then saturated with hydrogensulfide and filtered through a pad of filter aid. The resultant coloredfiltrate was evaporated to dryness and taken up in 50 ml. of methanol.By stirring for 20 minutes with 10 g. of neutral alumina and 2 g. ofdecolorizing carbon and then filtering, the solution was almostcompletely decolorized and gave upon evaporation to dryness the crudematerial which was purified by chromatography on fiorisil.Recrystallization of the solid fractions from acetone-ether gave5u,6,8-dichl0ro-19-nor-pregnane 3,8,- 16a,17a-triol-20-one-3-acetate.

To cc. of acetone containing 1 g. of the last named triol were added 30drops of 78% perchloric acid. After 1 hour at room temperature 30 dropsof pyridine were added and the resulting solution was evaporated todryness under reduced pressure. 30 cc. of water were added to theresidue and it was then extracted several times with 80 cc. of ethylacetate. The combined extracts were Washed to neutrality with water,dried over sodium sulfate and evaporated to dryness. The residue upontrituration with methanol gave a crude 16,17-acetonide.Recrystallization from the same solvent furnished 16a,- 17aisopropylidendioxy 5a,6{3-dichloro-l9-nor-pregnan-3fi-ol-20-one-acetate.

A suspension of l g. of the later steroid in 60 cc. of

methanol was treated with a solution of 1 g. of potassium carbonate in 6cc. of water; the mixture was boiled under reflux for 1 hour and thencooled in ice and diluted with water. The formed precipitate wascollected and recrystallized from acetone-hexane to yield16a,17a-is0propylidendioxy-Sa,'6;3%dichloro-19 nor-pregnan-3B-ol-20-one.

To a solution of 1 g. of the latter a,6{3-dichlorocompound in 200 cc. ofacetone, at room temperature and under a nitrogen atmosphere, there Wereadded, 60 cc. of freshly prepared chromous chloride solution. After 5minutes the acetone was removed under reduced pressure, water was addedand the precipitate filtered off and dried. Recrystallization fromacetone-hexane yielded 1604,1704- isopropylidendioxy-19-vnor-Apregnene-3[3-ol-20-one.

PREPARATION 3 A mixture of 6.6 g. of 19-nor-A -pregnen-3fi-ol-20-one,2.7 g. of p-toluenesulfonic acid and 300' cc. of acetic anhydride wassubmit-ted to a slow distillation; during 5 hours. The residue wascooled and poured into iced water. The product was then extracted withether, the extract washed successively with an aqueous solution ofsodium carbonate and water to neutral, dried and evaporated to dryness.The residue consisted of 19-nor- A -pregnadiene-3;3,2O/3-dioldiaceta-te, which was utilized in the following step withoutpurification.

6. g. of thisycrude diacetate were treated with 480 cc. of a 1.2 molarsolution of perbenzoic acid in benzene (2.2 molar equivalents) at roomtemperature and in the dark, for 20 hours. Water was then added, theorganic layer separated, washed with an aqueous solution of sodiumbicarbonate, then with water, dried with anhydrous sodium sulfate andevaporated to dryness. The residue consisted of the crude5a,6oc;17,20a-blSOXidO-19- nor-pregnane-35,20B-diol-diacetate.

This crude oxido compound was treated with 500 cc. of a 1% methanolicsolution of potassium hydroxide at room temperature for 1 hour, themixture was neutralized by addition of acetic acid, concentrated tosmall volume under reduced pressure, the product was precipitated byaddition of ice water, filtered off, washed with water, dried andrecrystallized from acetone-methanol, thus yielding 5a,6a oxido 19 norpregnane 3,8,17a diol 2O one-3-1acetate.

To 5 g. of the latter steroid in 80 cc. of glacial acetic acid, therewas added a mixture of 6 g. of sodium iodide, 1.6 g. of sodium acetate,320 mg. of zinc and 2 drops of water. While cooling in an ice bath andstirring, there were added to the resulting mixture, 800 mg. of zincdust in small portions. The stirring was continued for 6 hours and thetemperature allowed to attain 25 C.

The reaction mixture was filtered and the filtrate diluted with icewater, alkalized with sodium bicarbonate and extracted with ethylacetate. The extract was washed to neutral, dried over anhydrous sodiumsulfate and evaporated to dryness. Crystallization from acetone-hexaneyielded 19-n0r-A -pregnene,3[3,17ot-diol-2O-one3-acetate.

To a solution of 5 g. of the latter steroid in 100 cc. of anhydrousbenzene there were added 1 g. of p-toluenesulfonic acid and 10 cc. ofacetic anhydride and the mixture was allowed to stand for 24 hours atroom temperature, poured into ice and water, and the resulting mixturestirred to effect hydrolysis of the excess anhydride. The benzene layerwas separated and washed with 10% sodium carbonate solution and water.Drying, evaporation and crystallization of the residue from ether-hexaneproduced 19-nor-A -pregnene-3B,l7a-diol-20'-one-diacetate.

A suspension of 1 g. of the last named compound in 60 cc. of methanolwas treated with a solution of 1 g. of potassium carbonate in 6 cc. ofwater; the mixture was boiled under reflux for 1 hour and then cooled inice and diluted with water. The formed precipitate was collected andrecrystallized from acetone-hexane to yield 17a-acetoxy-19-nor-A-pregnen-3p-ol-2O-one.

PREPARATION 4 To a mixture of 1 g. of 50,6fl-di0l1l0f0-l911OI-Apregnen-3B-ol-20-one-racetate, l g. of cuprous chloride and 30 cc. ofanhydrous tetrahydrofuran was added, while stirring and cooling, 50 cc.of tetrahydrofuran containing 5' mol. equiv. of methyl magnesiumbromide.

The mixture was stirred for 2 hours at 28 C., then poured intoice-water, containing dilute hydrochloric acid. The product wasextracted with methylene chloride, the extract washed to neutral withwater and dried over anhydrous sodium sulfate. Evaporation of thesolvent at reduced pressure gave 'a residue, which was purified bycrystallization from methylene chloride-hexane to aiford16a-methyl-Sa,65-dichloro-19-nor-pregnan-3fi-0l-20-one.

The latter compound was treated with chromous chloride solution, asdescribed in Preparation 2, thus giving 16a-methyl-19-nor-A-pregnen-3B-ol-20-one, which upon conventional acetylation in pyridineafforded 16ot-methyl- 19-nor-A -pregnen-3fl-ol-20- one-acetate.

The latter acetate was treated in accordance with Preparation 3, thusgiving successively: l6a-methyl-l9-nor- A-pregnadiene-36,20fl-diol-diacetate, 16a methyl- 50,60t;170t,200L-biSOXld0-19 nor pregnane 35,206 dioldiacetate, 164x methyl 511,600 oxidol9 nor pregnane-3fi,17a-diol-20-one-3-acetate, 16oc-methyl-19-nor-Apregnene 35,170 diol 20 one 3 acetate, 16a methyl-l9-nor-A-pregnene-3B,17a-diol-2O one diacetate and 16ot-1I16thYl-l7ot-ZIC61LOXY- 19-nor-A -pregnen-3 fi-ol-20-one.

PREPARATION 5 A cooled solution of 4 g. of 16a,17a-isopropy1idendioxy-19-uor-A -pregnen-3B-ol-20-one in 30 cc. of tetrahydrofur-an and 18 'cc.of methanol was treated under continuous stirring with 6 g. of purecalcium oxide, in small portions, and then with '6 g. of iodine. Thestirring was continued at room temperature until the solution turnedpale yellow. The mixture was poured into ice water containing 18 cc. ofacetic acid and 2 g. of sodium thiosulfate. After stirring for 15minutes the solution was decanted and the precipitate was collected byfiltration, thus giving 21-;l0d0- 160.,17rx isopropylidendioxy 19 nor Apregnen 3,8- ol-ZO-one. f

The crude product was dried in vacuum, dissolved in 20 cc. ofacetonitrile and treated dr-opwise with 1.4 g. of silver fluoridedissolved in 3 cc. of water. After a short time, silver iodide startedto separate leaving the ZI-fiuQm-pregnan derivative in solution. Themixture was kept for 24 hours at room temperature and filtered.Concentration of the filtrate under vacuum gave a crude product whichafter crystallization from methanol acetone yielded 21fluoro-1'6a,l7u-isopropylidendioxy-19-1ror-A pregnen-3B-ol-20-one.

Following the same procedures 17a-acetoxy-19-nor-A pregnen-36-ol-20-oneand 16a-rnethyl-l7u=acetoxy-19-nor- A -pregnen-3B-ol-20-one wereconverted first into the corresponding 2l-iodo derivatives andthereafter respectively into 21 fluoro 17a-acetoxy-19-nor-A-pregnen-3p-ol-20- one and 1-6 wmethyl-21-fluoro-17u-acetoxy-19-n-or-A-pregnen-BB-ol-ZO-Dne.

Example I A mixture of 5 g. of 2lfluoro-16a-methyl-A -pregnen-3fi-ol-20-one (Petrow et al., J. Chem. Soc., 3595 (1959)), 150 cc. ofanhydrous benzene, 60 cc. of ethyleneglycol distilled over sodiumhydroxide and 0 mg. of p-toluenesulfonic acid monohydrate was refluxedfor 12 hours with the use of an adapter tor the continuous removal ofthe water formed during the reaction. Aqueous sodium bicarbonatesolution was added to the cooled mixture and the organic phase wasseparated, washed with water, dried over anhydrous sodium sulfate andevaporated to dryness. The residue crystallized from acetone-hexane togive 20 cycloethylenedioxy 21 fluoro 16a-methyl-A -pregnen- 35ml.

When applying the above procedure to the starting compounds listed underI there were obtained the products under II.

I II

16,17-acetnide. N-pregnen-BBJM,17a-triol-20cne- 16,17-acet0phenonidc.

Example II Starting compounds Products 20-cycloethylenedioxy-lh-acetoxy-16a-mcthyl-N-preg-nen-Iifi-ol.

20-cylcoethylenedioxy-lh-acetoxy- 1GB-methyl-N-pregnem3fl-ol.

20'cyeloethylenedioxy-Nwacetoxy- A -pregnen-3fl-ol.20-cycloethylenedioxy-lGa-methyl- A -preg'nen-3B-0l.20-cycloethylenedioxy-16Bmethyl- A -preg'nen-3B-0l.20-cycloethylenedioxy-ltlmor-A prcgnen-Bfl-ol. 20-cycloethylenedioxy-A-pregnen- 3B,16a,17a-triol-l6,l7-acetonide.

20-cycloethylenedioxy-M-pregnen- 3,8,16a,17a-trio1-16,17-acetophcnomde.acetophenonidc. 20-cycloethylenedioxy-Zl-fiuoro-M-20-cycloethylenedioxy-21-1'luor0- prcgnen-31S-0l.5a,6a-oxid0-pregnan-3-o1.

Example III To a solution of 80 cc. of 4 N methylmagnesium bromide inether was added, with stirring, a solution of 2 g. of 20cycloethylenedioxy 21 fiuoro-l6a-methyl-5u,6eloxido-pregnan-3 13-01, in60 cc. of dry tetrahydrofuran and the stirred mixture heated underreflux for 30 minutes. The condenser was then replaced by a calciumchloride tube, the ether allowed to boil off and when the internaltemperature reached 54 C., the condenser was readapted and the mixturerefluxed for an additional 4 hours. 400 cc. of a saturated solution ofammonium chloride was added slowly to the cooled mixture which was thenstirred for 15 minutes before transfer to a separatory funnel.

The tetrahydrofuran layer was separated, dried and ev aporated,whereupon crystallization of the residue from aqueout methanol gaveZO-cycloethylenedioxy-Zl-fluoro-QB,

16a-dimethyLpregnan-3[3,5tx-di01.

The starting compounds under I were treated following the above method,thus :afiording the corresponding products under II.

20-cycloethyleuedioxy-17aacetoxy- Illtfiaa-inethyl-m,dioxide-pregnan- -0ZO-cyeloethylenedioxy-Ua-acetoxy- :16B-inethy1-5a,fia-oxido-pregnan-Example IV A mixture of 1 :g. of ZO-cycloethylenedioxy-Zl-fluoro-6/3,16a-dimethyl-pregnan-3/3,5a-diol, 4 cc. of pyridine and 2 cc. ofacetic anhydride was kept at room temperature overnight, poured into icewater, the formed precipitate was filtered, washed with water and dried.Crystallization from acetone-hexanc gave 20-cycloethylenedioxy-21-fluoro-QB, 16 a-dimethyl-pregnan-3 [3,5 a-diol-B-acetate.

When applying the above technique to the starting compounds listedbelow, there were obtained the corresponding disclosed products.

Starting compounds Products 2O-cycloethylenedioxy-6 3-168-dimethyl-pregnan-bfl,5a-17a-trio1.

20-03 01oethylenedioxy-BB-acetoxy- 36,161+} imethyl-pregnan-MJM- 20cycloethylenedioxy-3B-acetoxy- 3?,TGB-dimethyl-pregnan-Sa,17a-

Example V Starting compounds Products 20-cycl0ethylenedioxy-SB-acetoxy-6g,16a-dimethyl-pregnan-5a,17o;-

diol. 20-cycloethylenedioxy-Zifl-acetoxy-3B,17a-diacetoxy-6,16a-di-methyl-A -pregnen-20-one.

Example VI products under II.

20-0ne 6,16B-dimethyl-A -pregnen-3fl-ol- 20-one.G-methyl-lQ-nor-N-pregnen-SB-ol- 20-one. 6-methyl-A-pregnen-3B,1601,1711- triol20one-l6,17-acetonide.

mde. G-methyl-Ql-fluoro-N-pregnen-3B- 01-20-one pregnen-20-one.

Example VII A solution of 5 g. of 21-fluoro-6,16a-dimethyl-A-pregnen-3fi-ol-20-one obtained in accordance with the foregoingexample, in 25 cc. of pyridine was cooled to C. Under stirring there wasadded 1.3 g. of tosyl chloride, the mixture was kept for 16 hours at 0C., diluted with 100 cc. of chloroform, washed with dilute hydrochloricacid, water, aqueous sodium bicarbonate solution and again with water,dried over anhydrous sodium sulfate and then evaporated to dryness underreduced pressure. Thus there wa-sobtained the crude 3-tosyl-ate of2l-fluoro-6,16ot dimethyI-A regnen-S,B-ol-ZO-one.

The total crude compound was refluxed with g. of anhydrous sodiumacetate and 60 cc. of glacial acetic acid during 2 hours. Chlorofior'mand water were added. The aqueous layer was extracted several times withchloroform and the combined'organic extracts were washed withconcentrated sodium bicarbonate solution then with water, dried oversodium sulfate and evaporated to dryness. Chromatography andrecrystallization of the solid fractions from acetone-hexane afiorded21-fiuoro-6;16a-dimethyl-A pregnadien-20-one.

The starting compounds listed below, were treated by the foregoingprocedures, thus yielding first the respective 3-tosylates and then thecorresponding products hereinafter disclosed.

Starting compounds Products 17a-acetoxy-6,16a-dimethy1-Apregnadien-ZO-one. 17a-acetoxy-SAGB-dimethyl-A pregnen-3fl-ol-20-one.pregnadien-ZO-one. 17a-acctoxy-fi-methyl-A -pregnen-17aacetoxy-6-methy1-A -pregna- 3 3-ol-200ne dien-ZO-one6,1fia-dimethyl-A -pregnen-3B-ol- SJGa-dimethyI-A -pregnadien-20-20-one. one. 6,16;?-dimethyl-A -pregnen-3fi-o1- 6,16a-dimethyl-A-pregnadien-2O- 20-one. one. 6-rnethyl-l9-n0r-A -pregnen-3B-ol-6-methyl-19-nor-A -pregnadien- 20-one. 20-0110.G-methyl-A-pregnen-313,16a,17a- 6-methy1-A-prcgnadien-lfiadhtriol-20-one-16,17-acetonide.diol-20-one-16,17-acetonide.

Example VIII A solution of 0.17 g. of potassium hydroxide in 0.2 cc. ofwater and 2.5 cc. of methanol was added over 30 minutes to a boilingsolution of 1 g. of 17a-acetoxy-5,l6adimethyl-A -pregnadien-ZO-one in 30cc. of methanol under an atmosphere of nitrogen. Boiling was continuedfor a further 2 hours and the solution was then cooled, neutralized withacetic acid and concentrated under reduced pressure. Addition of water,followed by crystallization of the precipitated solid fromacetone-hexane, produced 6,16a-dirnethyl-A 'Lpregnadien-17a-o1-20-one.

When applying the same technique to l7u-acetoxy-6, 16}8-dirnethyl-A-pregnadien-20-one and 17a-acetoxy-6- methyl A pregnadien-ZO-one, therewere respectively obtained 6,165 dimethyl n -pregnadien-l7-ot-ol-20-oneand 6-methy1-A -pregnadien-17a-ol-2O one.

Example IX To a solution of 5 g. of 6,16ot-dimethyl-A -pregnadiem17x-ol-20-one in cc. of anhydrous benzene there were added 1 .g. ofp-toluenesulfonic acid and 10 cc. of propionic anhydride and the mixturewas allowed to stand for 24 hours at room temperature, poured into iceand water, and the resulting mixture stirred to effect hydrolysis of theexcess anhydride. The benzene layer was separated and washed with 10%sodium carbonate solution and water. Drying, evaporation andcrystallization of the residue from ether-hexane produced6,16a-dirnethyl- A -pregna'dien-17u-ol-20 one-propionate.

Following the same procedure there were treated 6,16,8- vdimethyl-A-pregnadien-17u-ol-20-one and 6-methyl- A -pregnadien-17a-o1-20-onegiving respectively 6,165- dimethyl-Aipregnadien-17a-ol-20-one-propionate and 6- methyl-A-pregnadienl7ot-0l-20-OI1G-P1'OPlOH21t6.

Example X Using the same conditions as in the foregoing example butsubstituting propionic anhydride by caproic anhydride, there wereobtained 6,16u-dimethyl-A -pregnadien-17a- 01 20 one caproa-te, 6,1613dimethyl- A pregnadien 17a o1 2O one caproate and 6 methyl A pregnadien17a ol 20 one caproate.

Example XI 1 g. of 6-methyl-A -pre-gnadien-16a,17uadiol-2O one-16,17-acetonide was heated on the steam bath with 20 cc. of 60% formicacid for 1 hour, cooled, diluted with water and the precipitate wascollected, washed with water, dried, and recrystallized fromacetone-hexane, thus afiording 6-methy1-A-pregnadien-16u,17u-diol-20-one.

1 1 Example XII A mixture of 1 g. of the foregoing compound, 4 cc. ofpyridine and 2 cc. of acetic anhydride was kept at room temperatureovernight, poured into ice water, the formed precipitate was filtered,washed with water and dried. Crystallization from acetone-hexane gave 6methyl-A -pregnadien-16a, 17a-diol-20-onel 6-acetate.

Example XIII The latter compound was treated following the techniquedescribed in Example X, thus yielding 6-methyl-Apregnadien-l6a,17a-diol-20-one-16-acetate-l7-caproate.

Example XIV 6-methyl-A -pregnadien-l6a,17a-diol-20 one was treatedfollowing the procedure delineated in Example IX, thus yielding6-methyl-A -pregnadien-l6a,17a-diol-2O- one-16,17-dipropionate.

Example XV 2 g. of the preceding dipropionate were dissolved in 50 cc.of methanol and treated with 5 cc. of a 4% aqueous solution of potassiumhydroxide; the reaction mixture was stirred for 1 hour under anatmosphere of nitrogen at C.; the mixture was neutralized with aceticacid and the methanol distilled under reduced pressure. The residue wastriturated with water and the solid collected, washed with water, driedand recrystallized from ethyl acetatemethanol, thus producing 6-methyl-A-pregnadien-16a, 17a-diol-20-one-17-propionate.

Example XVI The latter monoester was acetylated by the proceduredescribed in Example XII, thus yielding 6-methyl-A pregnadien 16a,l7udiol one 16 acetate 17- propionate.

Example XVII l6a,l7a isopropylidendioxy l9-nor-A -pregnen-3,8-0l- 20-onewas successively treated in accordance with Examples I, II, III, IV, V,VI, VII and XI thus affording respectively 16a,170c isopropylidendioxy20 cycloethylene-dioxy- 19-nor-A apregnen-3B-o1,

16a,17cc isopropylidendioxy 20 cycloethylenedioxy-5a,6a-oxido-19-nor-pregnan-3/3-ol,

160:,17uc isopropylidendioxy 20 cycloethylenedioxy-Gfl-methyl-19-nor-pregnane 313,5a-di0l,

16a,17uc isopropylidendioxy 2O cycloethylenedioxy-6,8-methyl-19-nor-pregnane-3,8,5oc-diol-3-acetate,

16oz,170c isopropylidendioxy-6-methyl-19-nor-A -pregncn-3,8-ol-20-one-acetate,

16ot,17a isopropylidendioxy 6 methyl 19* nor A pregnen-3/3-ol-20-one,

l6a,17a isopropylidendioxy 6 methyl l9 nor A pregnadien-ZO-one and 6methyl 19 nor A pregnadiene 16ol,17oc diol- 20-one.

Example XVIII 17a acetoxy 19 nor A pregnen 3 8 ol 20 one was treatedfollowing consecutively the procedures described in Examples I, II, III,IV, V, VI, VII and VIII, giving respectively 20 cycloethylenedioxy17oz-acetoxy-l9-nor-A -pregnen- 35-01, 20 cycloethylenedioxy17a-acetoxy-5a,6a-oxido-19-norpregnan-Iap-ol, 2O cycloethylenedioxyG/R-methyl-l9 nor-preg-nane-3,8,

5 u, 17oc-tli01, 20 cycloethylenedioxy 6,8-methyl-l9-nor-pregnane-35,

5a, 17a-trio1-3-acetate, 3,8,l7a-diacetoxy-6-methyl-l9-nor-A-pregnen-20-one, 17a-acetoxy-6-methyl-19-nor-A -pregnen-3B-ol-20-one,17a-a-cetoxy-6-methyl-19-nor-A @pregnadien-ZO-one and 6-methyl-19-nor-A-pregnadien-17a-ol-20-one.

1 2 Example XIX l6a-methyl-17a-acetoxy-19-n0r-A -pregnen-3,8-ol20-onewas successively treated according to Examples I, II, III, IV, V, VI,VII and VIII, yielding respectively 20- cyclo ethylenedioxyl7 a-acetoxy-1 6 a-methyl- 19-nor-A pregnen-3 B-rol,

20-eycloethylenedioxy- 1 7aacetoxy-1 6a-methyl-5 a, 6 aoxido- 19-nor-pregnan-3 5-101,

20-cyclo ethyl ene-dioxy-6 [3, 1 6a-dimethyl- 19-nor-pregnane-3,6,5a,17u-trio1,

20=cycloethy1enedioxy-6 8, l6a-dimethyl-19-nor-prcgmane-3 ,8, 5 a,l7a-triol-3 acetate,

3 p, 17 a-diacetoxy-6, 16 a-dimethy-l-l 9-nor-A pregnen- 20-one,

l7aaacetoxy-6, 16a-dimethyl-19-nor-A -pregnen-3B-ol- ZO-one,

17 a-acetoxy-6, l6 a-dimethyl-19-nor-A -pregnadienr 20-one and 6,16a-dimethyl-l9-n-0r-A -pregnadien-1704*01-20-0118.

Example XX 21-fluono-16a,17a-isopnopylidendioxy-l9-nor-Apregnen-Sfi-zol-ZO-one was successively treated in accordance withExamples I, II, III, IV, V, VI, VII and XI thus affording respectively2l-fluoro-l6a,17a-isopropylidendioxy-ZO-cycloethylenedioxy-l9-nor-n-pregnen-3paol,

2l-fluono-16a, l 7a-isopropylidendioxy-ZO-cycloethylenedioxy-5a,6a-oxido-19-nor-pregnan-3,B-ol,

2 l-fluoro-l 60c,17a-isopnopylidendioxy-20-cycloethylcnedioxy-6/3-methyl-19-nor-pregnane-3Bjaadiol,

21-fiuoro-l6a, l 7oc-iS op-rop ylidendioxy-Z O-cycloethylenedioxy-6,8-methyl-l9-nor-pregnane-35,5a-diol-3acetate,

2 1-fluoro-16 a, 17a-iS o-propylidendioxy-6-methyl-19-nor- A-pregnen-35-ol-20=one-acetate,

21fluoro-16a, 17 a-i sopropylidendioxy-6-methyl- 19-nor- Apregnen-3B-ol-20-one,

21 -fluoro- 1 6 a, 17a-isopnopylidendioxy-6-methyl-19-nor- A-pregnadien-20-one and Example XXI Example XXII2l-fluoro-l6a-methyl-17a-acetoxy-19-nor-A pregnem 3,8-ol-20-one wassuccessively treated according to Examples I, II, III, IV, V, VI, VIIand VIII yielding respectively 21-fiuoro-20-cycloethylenedioxy-6B,16a-dimethyl-19-norpregnane-3 5,5 a, 17a-LIiOl-3 acetate,

21-flu-oro-3 5, 17 a diacetoxy-6, 16 u-1dimethyl-19-n0r-Apregnen-ZO-one,

21-fiuoro-17uacetoxy6,16a-dimethy l-19-nor-A -pregnadien-ZO-one and21-fluoro-6,16a-dimethyl-19-nor-A -pregnadien-17a-ol- 20-one.

We claim: 1. A compound of the following formula:

$H2Y 0:0 I. a

MNRZ

14 wherein P is a lower alkyl gnoup and Q is selected from the groupconsisting of a lower lalkyl, an aryl and an ar-alkyl group, eachcontaining up to 8 carbon atoms.

. 17a1acetoxy-6,16a-dimethyl-M' -pregnadien-20cne. 17 (X-alCetOXy-6,16fl-dimethyl-A -pregnadien-20-cne. 17a-acetoxy-6methyl-A-pregnadien-20-one. 6, 1 6a-dimethyl-A -pregnadien-20-one.6,16fl-dimethyl-A -prcgnadien-20-one. 6-methyl-19-nor-A-pregnadien-20-one.

8. 6 methyl- A pregnadien 16a,17 x diol 20- one-16,17-acetonide.

9. 6 methyl A pregnadien 1611,1711; diol 20- one-l 6,17-acetophenonide.

10. 6 methyl A pregnadien 1604.170 diol 20- one-17-propionate.

11. 6 methyl A one-16,17-dipropionate.

12. 6 methyl A pregna'dien-16a,17a1diol-20-one- 16-acetate-17-caproate.

13. 6 methyl A pregnadien 16a,17oz diol 20- one-l 6-acetate- 17-pr0pionate.

14. 21-fiu0r0-6,16a-dimethyl-A -pregnadien-2O-one.

15. 21-fluoro-6-methyl-A -pregnadien-20-one.

16. in the process for the production of 6-methyl-A pregnadienederivatives the steps which comprise treating the corresponding3fl-hydroxy-6-methyl-A -pregnene with a lower hydrocarbon sulfonic acidchloride in a tertiary amine and treating the resultant 3fl-sulfonatewith an alkali metal lower hydrocarbon carboxylic acylate in a lowerhydrocarbon carboxylic acid.

17. The process of claim 16 wherein the lower hydrocarbon sulfonic acidchloride is p-toluenesulfonic acid chloride, the tertiary amine ispyridine, the alkali metal lower hydrocarbon carboxylic 'acylate issodium acetate and the lower hydrocarbon carboxylic acid is acetic acid.

- pregnadien 1601.170: diol 20- No references cited.

1. A COMPOUND OF THE FOLLOWING FORMULA:6-(H3C-),16,17-DI(R2-),20-(O=),21-Y-PREGN-3,5(6)-DIENE WHEREIN Y ISSELECTED FROM THE GROUP CONSISTING OF HYDROGEN AND FLUORINE; R1 IS AMEMBER OF THE GROUP CONSISTING OF HYDROGEN AND METHYL; R2 IS SELECTEDFROM THE GROUP CONSISTING OF HYDROXYL AND A HYDROCARBON CARBOXYLICACYLOXY GROUP OF LESS THAN 12 CARBON ATOMS; R3 IS A MEMBER OF THE GROUPCONSISTING OF HYDROGEN, A-METHYL, B-METHYL, A-HYDROXYL AND ANA-HYDROCARBON CARBOXYLIC ACYLOXY GROUP OF LESS THAN 12 CARBON ATOMS; R2AND R3 TOGETHER ARE IN ADDITION, THE GROUP -O-C(-P)(-Q)-OWHEREIN C19=R1WHEREIN P IS A LOWER ALKYL GROUP AND Q IS SELECTED FROM THE GROUPCONSISTING OF A LOWER ALKYL, AN ARYL AND AN ARALKYL GROUP, EACHCONTAINING UP TO 8 CARBON ATOMS.